Glaucomatous optic neuropathy, the second leading cause of permanent blindness in the United States, is associated with an increased rate of retinal ganglion cell death. Epidemiological studies have shown that elevated intraocular pressure (IOP) is the most common risk factor associated with primary open angle glaucoma, the most common form of the disease. It is hypothesized that chronically elevated IOP creates a pressure gradient along the course of exiting optic nerve axons, and thereby interferes with axonal transport or circulation, ultimately causing death of retinal ganglion cells.
Because there is a high correlation between glaucomatous optic neuropathy and increased IOP, strategies for treating glaucomatous optic neuropathy have been directed almost exclusively toward methods of reducing IOP. Currently, the pharmacological treatment of choice consists primarily of the topical application of ocular hypotensive agents (Sugrue, Pharmacol. Ther. 43:91-138, 1989).
Despite their widespread use in the treatment of glaucomatous optic neuropathy, ocular hypotensive agents are not effective in treating a large percentage of people with glaucomatous optic neuropathy. Many people with glaucomatous optic neuropathy have a normal IOP. From 30-50% of people with open angle glaucoma do not initially have ocular hypertension, and as many as 15-50% of patients with glaucomatous optic neuropathy do not have elevated IOP. Therefore, considerable effort has been directed toward developing suitable methods for treating glaucomatous optic neuropathy in patients with normal or high IOP, as well as for treating several other optic neuropathies that are not associated with increased IOP. The absence of increased IOP in certain glaucomatous optic neuropathy patients suggests that there is at least one mechanism other than elevated intraocular pressure that contributes to the optic neuropathy associated with glaucomatous optic neuropathy (Levin, Current Opinion in Ophthalmology 8:9-15, 1997; Levin, Mediguide to Ophthalmology 8:1-5, 1999).
Knowledge of mechanisms responsible for natural and experimental optic neuropathy, including axonal transection, optic nerve crush and optic nerve ischemia, may facilitate development of suitable treatments for glaucomatous optic neuropathy and other optic neuropathies affecting the axons of retinal ganglion cells, including ischemic optic neuropathy, inflammatory optic neuropathy, compressive optic neuropathy,and traumatic optic neuropathy. Each of these conditions likely causes apoptosis. The mechanism responsible for initiating apoptosis in retinal ganglion cells has not been unequivocably established. However, it is speculated that decreased retrograde transport of neurotropic factors, decreased levels of endogenous ocular neurotrophins, or any one of several other mechanisms may trigger apoptosis.
U.S. Pat. No. 5,667,968, incorporated herein by reference, discloses the use of ciliary neurotrophic factor (CNTF) and other neurotrophic factors to prevent injury or death of retinal neurons. The neurotrophic factors may be administered intraocularly or into the vitreous of the eye.
Neurotrophin deprivation may initiate at least one of several cytotoxic cellular mechanisms. Such mechanisms include, without limitation, excitotoxicity, reactions catalyzed or signaled by reactive oxygen species, mitochondrial depolarization, mitochondrial release of apoptosis-inducing factors, and elevation of intracellular calcium concentrations to toxic levels.
Therapeutic agents useful in inhibiting cell death induced or initiated by cytotoxic mechanisms have been identified in preliminary studies using model systems. For example, glutamate receptor antagonists (including dextromethorphan, NMDA antagonists, and aspartate antagonists) may be used to protect against excitotoxicity. Reactive oxygen species scavengers (e.g., superoxide dismutase and catalase) and antioxidants (e.g., vitamin E and D-mannitol) may be used to quench specific reactive oxygen species. Calcium channel blockers such as dihydropyridines may be used to reduce toxic intracellular calcium levels.
What is needed in the art is a new method for treating glaucomatous optic neuropathy and other eye diseases affecting the retinal ganglion cells.